Circulating High Mobility Group Box-1 Does Not Predict Pulmonary Arterial Hypertension in Children with Congenital Heart Disease: A Prospective Cohort Study.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a devastating complication of pediatric congenital heart disease (CHD). A recent study has identified the protein high mobility group box-1 (HMGB1) as a diagnostic tool in adults with CHD-associated PAH. HMGB1 levels in adults with CHD-associated PAH correlated with mean pulmonary artery pressure and pulmonary vascular resistance, and HGMB1 levels fell in response to sildenafil therapy. We wanted to assess if HGMB1 was a biomarker of pediatric CHD-PAH. DESIGN: Prospective cohort study. SETTING: Quaternary pediatric academic hospital PARTICIPANTS: Children ≤18 years with CHD with and without known pulmonary hypertension. Controls were children undergoing dental or urologic surgery with no known heart disease. INTERVENTIONS: Pulmonary hemodynamics, echocardiographic assessment, and biomarker measurement. Controls had biomarker measurement only. MEASUREMENTS AND MAIN RESULTS: Patients with CHD-PAH had mean pulmonary vascular resistance index of 10 Wood units/m2. Neither HGMB1 nor N-terminal pro-brain-type natriuretic peptide levels were significantly different between the groups. Neither marker correlated with pulmonary hypertension. CONCLUSIONS: Unlike in adults, HGMB1 is not a biomarker of PAH in pediatric CHD. Further work will continue to explore for biomarkers for this high-risk population.

NINJ1 mediates plasma membrane rupture by cutting and releasing membrane disks.

The membrane protein NINJ1 mediates plasma membrane rupture in pyroptosis and other lytic cell death pathways. Here, we report the cryo-EM structure of a NINJ1 oligomer segmented from NINJ1 rings. Each NINJ1 subunit comprises amphipathic (⍺1, ⍺2) and transmembrane (TM) helices (⍺3, ⍺4) and forms a chain of subunits, mainly by the TM helices and ⍺1. ⍺3 and ⍺4 are kinked, and the Gly residues are important for function. The NINJ1 oligomer possesses a concave hydrophobic side that should face the membrane and a convex hydrophilic side formed by ⍺1 and ⍺2, presumably upon activation. This structural observation suggests that NINJ1 can form membrane disks, consistent with membrane fragmentation by recombinant NINJ1. Live-cell and super-resolution imaging uncover ring-like structures on the plasma membrane that are released into the culture supernatant. Released NINJ1 encircles a membrane inside, as shown by lipid staining. Therefore, NINJ1-mediated membrane disk formation is different from gasdermin-mediated pore formation, resulting in membrane loss and plasma membrane rupture.

Bilateral nephrectomy impairs cardiovascular function and cerebral perfusion in a rat model of acute hemodilutional anemia.

Anemia and renal failure are independent risk factors for perioperative stroke, prompting us to assess the combined impact of acute hemodilutional anemia and bilateral nephrectomy (2Nx) on microvascular brain Po2 (PBro2) in a rat model. Changes in PBro2 (phosphorescence quenching) and cardiac output (CO, echocardiography) were measured in different groups of anesthetized Sprague-Dawley rats (1.5% isoflurane, n = 5-8/group) randomized to Sham 2Nx or 2Nx and subsequently exposed to acute hemodilutional anemia (50% estimated blood volume exchange with 6% hydroxyethyl starch) or time-based controls (no hemodilution). Outcomes were assessed by ANOVA with significance assigned at P < 0.05. At baseline, 2Nx rats demonstrated reduced CO (49.9 ± 9.4 vs. 66.3 ± 19.3 mL/min; P = 0.014) and PBro2 (21.1 ± 2.9 vs. 32.4 ± 3.1 mmHg; P < 0.001) relative to Sham 2Nx rats. Following hemodilution, 2Nx rats demonstrated a further decrease in PBro2 (15.0 ± 6.3 mmHg, P = 0.022). Hemodiluted 2Nx rats did not demonstrate a comparable increase in CO after hemodilution compared with Sham 2Nx (74.8 ± 22.4 vs. 108.9 ± 18.8 mL/min, P = 0.003) that likely contributed to the observed reduction in PBro2. This impaired CO response was associated with reduced fractional shortening (33 ± 9 vs. 51 ± 5%) and increased left ventricular end-systolic volume (156 ± 51 vs. 72 ± 15 µL, P < 0.001) suggestive of systolic dysfunction. By contrast, hemodiluted Sham 2Nx animals demonstrated a robust increase in CO and preserved PBro2. These data support the hypothesis that the kidney plays a central role in maintaining cerebral perfusion and initiating the adaptive increase in CO required to optimize PBro2 during acute anemia.NEW & NOTEWORTHY This study has demonstrated that bilateral nephrectomy acutely impaired cardiac output (CO) and microvascular brain Po2 (PBro2), at baseline. Following acute hemodilution, nephrectomy prevented the adaptive increase in CO associated with acute hemodilution leading to a further reduction in PBro2, accentuating the degree of cerebral tissue hypoxia. These data support a role for the kidney in maintaining PBro2 and initiating the increase in CO that optimized brain perfusion during acute anemia.